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Accelerated proliferation of myeloma cells by interleukin-6 cooperating with fibroblast growth factor receptor 3-mediated signals

Oncogene volume 24, pages 6328–6332 (2005)Cite this article

Abstract

Interleukin-6 (IL-6) is a cytokine that regulates the proliferation of some tumor cells including multiple myeloma (MM). Ectopic expression of fibroblast growth factor receptor 3 (FGFR3) associated with the chromosomal translocation, t(4;14)(p16.3;q32), is frequently found in MM, and therefore, has been implicated in the neoplastic transformation of this disease. Here, we show that IL-6 together with FGF enhanced proliferation of a myeloma cell line, KMS-11 carrying t(4;14)(p16.3;q32) and the FGFR3-transfected U266 myeloma cell line which ectopically expressed FGFR3 but responded to neither IL-6 nor FGF alone. In KMS-11, IL-6 activated signal transducer and activator of transcription 3 (STAT3) while FGF activated extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol (PI)-3 kinase. As both MEK inhibitors and a PI 3-kinase inhibitor abolished the effect of IL-6 and FGF, the activation of both the ERK1/2 and PI 3-kinase signaling cascades is essential for the proliferation of KMS-11 enhanced by IL-6 and FGF. Furthermore, the FGF-induced activation of ERK1/2 contributed to the serine phosphorylation of STAT3, suggesting that the signaling crosstalk between the cytokine receptor, IL-6 receptor α/gp130 and the growth factor receptor tyrosine kinase, FGFR3. These results indicate that FGFR3 plays a crucial role in the accelerated proliferation of MM carrying t(4;14)(p16.3;q32).

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Acknowledgements

KMS-11 and KMS-18 were kindly provided by Proferssor Takemi Otsuki (Kawasaki Medical School, Kurashiki, Japan). We thank Dr Harumi Suzuki (Yamaguchi University) and Prof. Toshio Hirano (Osaka University, Osaka, Japan) for generous gift of pRep and 4xAPRE SpLuc, respectively. We also thank the Center for Gene Research, Yamaguchi University for DNA sequencing. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, the Ministry of Health, Labor and Welfare of Japan, the Japan Society for the Promotion of Science (JSPS), the Yamanouchi Foundation for Research on Metabolic Disorders, Public Trust Haraguchi Memorial Cancer Research Fund and International Myeloma Foundation. JSPS Postdoctoral Fellowship for Foreign Researchers (P04500) awarded to SA.

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  1. Department of Bio-Signal Analysis, Laboratory of Cellular Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, 755-8505, Yamaguchi, Japan

    Hideaki Ishikawa, Naohiro Tsuyama, Shangqin Liu, Saeid Abroun, Fu-Jun Li, Ken-ichiro Otsuyama, Xu Zheng, Zi Ma, Yasuko Maki, Mohd S Iqbal, Masanori Obata & Michio M Kawano

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  1. Hideaki Ishikawa
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Correspondence to Hideaki Ishikawa.

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Ishikawa, H., Tsuyama, N., Liu, S. et al. Accelerated proliferation of myeloma cells by interleukin-6 cooperating with fibroblast growth factor receptor 3-mediated signals. Oncogene 24, 6328–6332 (2005). https://doi.org/10.1038/sj.onc.1208782

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